3-azabicyclo(3.1.0)hexane-2-carboxylic acid has been found to be an effective plant male gametocide: U.S. Pat. No. 4,047,930 (the compound is designated therein as 2-carboxy-3,4-methanopyrrolidine). The compound exists in the forms of two geometric (i.e., cis, trans) isomers. Each of these isomeric forms exists in the forms of optical isomers. The racemic mixtures of both of the geometric isomers are active as plant male gametocides. The naturally occurring L,cis isomer is active as a plant male gametocide; the relative activities of each of the other optical isomer forms have not been determined. The L,cis isomer occurs naturally in the seeds of the American horse chestnut, Aesculus parviflora.
3-azabicyclo(3.1.0)hexane-2-carboxylic acid now can be prepared synthetically by the following route:
(1) cis-ethyl 2-cyanocyclopropylcarboxylate (Zhur. Org. Knim., 7, 2108 et seq. (1971)) is treated with sodium hydroxide and the product is acidified to spring the acid.
(2) The acid is treated with oxalyl chloride in benzene to form the crude 2-cyanocyclopropyl acid chloride.
(3) The crude acid chloride is treated with a reducing agent, such as tri-(tertiary-butoxy) lithium aluminum hydride, in tetrahydrofuran, at a low temperature (e.g., -60.degree. C.) to form crude 2-cyanocyclopropyl aldehyde.
(4) The crude (or separated) aldehyde is refluxed with an alkanol to form the acetal.
(5) The acetal is treated with a reducing agent, such as lithium aluminum hydride, in tetrahydrofuran, to give the cis 2-aminomethylcyclopropyl-1,1-dialkylacetal.
(6) The acetal is added to a cyanide in the presence of a liquid alkanecarboxylic acid to form the N-alkanoyl-3-azabicyclo(3.1.0)-hexane-2-carbonitrile.
(7) The nitrile is treated with a strong inorganic acid to give the N-alkanoyl-3-azabicyclo(3.1.0)hexane-2-carboxylic acid.
(8) The acid is treated with a strong inorganic acid to give 3-azabicyclo(3.1.0)hexane-2-carboxylic acid, as the salt of the inorganic acid.
Steps 7 and 8 can be combined, and effected without isolation of the N-alkanoyl intermediate.
(9) The free acid can be prepared from the salt by conventional procedures.